http://purl.uniprot.org/citations/23368879 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
http://purl.uniprot.org/citations/23368879 | http://www.w3.org/2000/01/rdf-schema#comment | "BackgroundAlzheimer's disease (AD) is intimately tied to amyloid-β (Aβ) peptide. Extraneuronal brain plaques consisting primarily of Aβ aggregates are a hallmark of AD. Intraneuronal Aβ subunits are strongly implicated in disease progression. Protein sequence mutations of the Aβ precursor protein (APP) account for a small proportion of AD cases, suggesting that regulation of the associated gene (APP) may play a more important role in AD etiology. The APP promoter possesses a novel 30 nucleotide sequence, or "proximal regulatory element" (PRE), at -76/-47, from the +1 transcription start site that confers cell type specificity. This PRE contains sequences that make it vulnerable to epigenetic modification and may present a viable target for drug studies. We examined PRE-nuclear protein interaction by gel electrophoretic mobility shift assay (EMSA) and PRE mutant EMSA. This was followed by functional studies of PRE mutant/reporter gene fusion clones.ResultsEMSA probed with the PRE showed DNA-protein interaction in multiple nuclear extracts and in human brain tissue nuclear extract in a tissue-type specific manner. We identified transcription factors that are likely to bind the PRE, using competition gel shift and gel supershift: Activator protein 2 (AP2), nm23 nucleoside diphosphate kinase/metastatic inhibitory protein (PuF), and specificity protein 1 (SP1). These sites crossed a known single nucleotide polymorphism (SNP). EMSA with PRE mutants and promoter/reporter clone transfection analysis further implicated PuF in cells and extracts. Functional assays of mutant/reporter clone transfections were evaluated by ELISA of reporter protein levels. EMSA and ELISA results correlated by meta-analysis.ConclusionsWe propose that PuF may regulate the APP gene promoter and that AD risk may be increased by interference with PuF regulation at the PRE. PuF is targeted by calcium/calmodulin-dependent protein kinase II inhibitor 1, which also interacts with the integrins. These proteins are connected to vital cellular and neurological functions. In addition, the transcription factor PuF is a known inhibitor of metastasis and regulates cell growth during development. Given that APP is a known cell adhesion protein and ferroxidase, this suggests biochemical links among cell signaling, the cell cycle, iron metabolism in cancer, and AD in the context of overall aging."xsd:string |
http://purl.uniprot.org/citations/23368879 | http://purl.org/dc/terms/identifier | "doi:10.1186/1471-2164-14-68"xsd:string |
http://purl.uniprot.org/citations/23368879 | http://purl.uniprot.org/core/author | "Lahiri D.K."xsd:string |
http://purl.uniprot.org/citations/23368879 | http://purl.uniprot.org/core/author | "Rogers J.T."xsd:string |
http://purl.uniprot.org/citations/23368879 | http://purl.uniprot.org/core/author | "Ge Y.W."xsd:string |
http://purl.uniprot.org/citations/23368879 | http://purl.uniprot.org/core/author | "Maloney B."xsd:string |
http://purl.uniprot.org/citations/23368879 | http://purl.uniprot.org/core/date | "2013"xsd:gYear |
http://purl.uniprot.org/citations/23368879 | http://purl.uniprot.org/core/name | "BMC Genomics"xsd:string |
http://purl.uniprot.org/citations/23368879 | http://purl.uniprot.org/core/pages | "68"xsd:string |
http://purl.uniprot.org/citations/23368879 | http://purl.uniprot.org/core/title | "PuF, an antimetastatic and developmental signaling protein, interacts with the Alzheimer's amyloid-beta precursor protein via a tissue-specific proximal regulatory element (PRE)."xsd:string |
http://purl.uniprot.org/citations/23368879 | http://purl.uniprot.org/core/volume | "14"xsd:string |
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